NM_014846.4:c.3291G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_014846.4(WASHC5):c.3291G>A(p.Ala1097Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,613,874 control chromosomes in the GnomAD database, including 6,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 3087 hom., cov: 30)

Exomes 𝑓: 0.045 ( 3820 hom. )

Consequence

WASHC5
NM_014846.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.71

Publications

8 publications found

Variant links:

Genes affected

WASHC5 (HGNC:28984): (WASH complex subunit 5) This gene encodes a 134 kDa protein named strumpellin that is predicted to have multiple transmembrane domains and a spectrin-repeat-containing domain. This ubiquitously expressed gene has its highest expression in skeletal muscle. The protein is named for Strumpell disease; a form of hereditary spastic paraplegia (HSP). Spastic paraplegias are a diverse group of disorders in which the autosomal dominant forms are characterized by progressive, lower extremity spasticity caused by axonal degeneration in the terminal portions of the longest descending and ascending corticospinal tracts. More than 30 loci (SPG1-33) have been implicated in hereditary spastic paraplegia diseases. [provided by RefSeq, Aug 2009]

WASHC5 Gene-Disease associations (from GenCC):

Ritscher-Schinzel syndrome 1
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hereditary spastic paraplegia 8
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Ritscher-Schinzel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WASHC5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 8-125032285-C-T is Benign according to our data. Variant chr8-125032285-C-T is described in ClinVar as Benign. ClinVar VariationId is 129376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.71 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC5	NM_014846.4	MANE Select	c.3291G>A	p.Ala1097Ala	synonymous	Exon 27 of 29	NP_055661.3
	WASHC5	NM_001330609.2		c.2847G>A	p.Ala949Ala	synonymous	Exon 26 of 28	NP_001317538.1	E7EQI7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WASHC5	ENST00000318410.12	TSL:1 MANE Select	c.3291G>A	p.Ala1097Ala	synonymous	Exon 27 of 29	ENSP00000318016.7	Q12768
WASHC5	ENST00000920325.1		c.3339G>A	p.Ala1113Ala	synonymous	Exon 27 of 29	ENSP00000590384.1
WASHC5	ENST00000890504.1		c.3291G>A	p.Ala1097Ala	synonymous	Exon 28 of 30	ENSP00000560563.1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20438

AN:

151968

Hom.:

3064

Cov.:

show subpopulations

Gnomad AFR

AF:

0.373

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0669

Gnomad ASJ

AF:

0.0309

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0918

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0380

Gnomad OTH

AF:

0.111

GnomAD2 exomes

AF:

0.0609

AC:

15303

AN:

251232

AF XY:

0.0546

show subpopulations

Gnomad AFR exome

AF:

0.382

Gnomad AMR exome

AF:

0.0401

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0842

Gnomad NFE exome

AF:

0.0403

Gnomad OTH exome

AF:

0.0556

GnomAD4 exome

AF:

0.0451

AC:

65864

AN:

1461788

Hom.:

3820

Cov.:

AF XY:

0.0439

AC XY:

31909

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.387

AC:

12937

AN:

33460

American (AMR)

AF:

0.0439

AC:

1965

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0332

AC:

867

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0207

AC:

1785

AN:

86258

European-Finnish (FIN)

AF:

0.0784

AC:

4188

AN:

53414

Middle Eastern (MID)

AF:

0.0862

AC:

497

AN:

5766

European-Non Finnish (NFE)

AF:

0.0361

AC:

40105

AN:

1111940

Other (OTH)

AF:

0.0583

AC:

3518

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3355

6709

10064

13418

16773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1624

3248

4872

6496

8120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.135

AC:

20509

AN:

152086

Hom.:

3087

Cov.:

AF XY:

0.134

AC XY:

9932

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.373

AC:

15473

AN:

41438

American (AMR)

AF:

0.0669

AC:

1024

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0309

AC:

107

AN:

3466

East Asian (EAS)

AF:

0.000388

AC:

AN:

5156

South Asian (SAS)

AF:

0.0183

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0918

AC:

972

AN:

10584

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0380

AC:

2581

AN:

68002

Other (OTH)

AF:

0.109

AC:

231

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

748

1496

2245

2993

3741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0725

Hom.:

1846

Bravo

AF:

0.143

Asia WGS

AF:

0.0420

AC:

146

AN:

3478

EpiCase

AF:

0.0394

EpiControl

AF:

0.0452

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 8 (2)

not specified (2)

Hereditary spastic paraplegia (1)

not provided (1)

Ritscher-Schinzel syndrome;C1863704:Hereditary spastic paraplegia 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

0.17

(source)

DANN

Benign

0.89

PhyloP100

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over